As reported in Chemical Week on Sept. 18, 1985 at pages 13-14, there is a considerable need for a simple, inexpensive and non-polluting route to guanidines. Guanidines constitute an important class of organic compounds useful for various medical and agricultural purposes including hypoglycemic agents for the treatment of diabetes.
The present invention also relates to the synthesis of guanidine compounds such as the anti-diabetic compound linogliride or N-(1-methyl-2-pyrrolidinylidene)-N'-phenyl-4-morpholinecarboximidamide and includes synthetic steps and intermediates.
Linogliride fumarate (CAS Registry No. 78782-47-5) is a hypoglycemic compound and is disclosed in U.S. Pat. No. 4,211,867. It is an object of the present invention to provide a high yield, facile and short synthesis of linogliride with by products and reagents which are comparatively safe and easily handled.
At column 11 of U.S. Pat. No. 4,211,867 there is described a method of making a N,N'-disubstituted guanidine intermediate by reacting an N-substituted thiourea with an alkylating agent to produce the corresponding alkylthio compound which is then reacted with an amine to displace mercaptan. Such a route has the disadvantage of removal and disposal of malodorous mercaptans.
Oxidations of thioureas are found in U.S. Pat. Nos. 4,210,658; 4,275,896 and 4,381,395, U.K. Pat. No. 1,586,258; U.S.S.R. Pat. No. 178,803 published Feb. 3, 1966 and by W. Walter and G. Randau in Liebigs Ann. Chem. 722, pages 98-109 (1969).